Screening of the ‘Open Scaffolds’ collection from Compounds Australia identifies a new chemical entity with anthelmintic activities against different developmental stages of the barber's pole worm and other parasitic nematodes

Sarah Preston, Yaqing Jiao, Jonathan B. Baell, Jennifer Keiser, Simon Crawford, Anson V Koehler, Tao Wang, Moana M. Simpson, Ray M. Kaplan, Karla J. Cowley, Kaylene J Simpson, Andreas Hofmann, Abdul Jabbar, Robin Beat Gasser

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The discovery and development of novel anthelmintic classes is essential to sustain the control of socioeconomically important parasitic worms of humans and animals. With the aim of offering novel, lead-like scaffolds for drug discovery, Compounds Australia released the ‘Open Scaffolds’ collection containing 33,999 compounds, with extensive information available on the physicochemical properties of these chemicals. In the present study, we screened 14,464 prioritised compounds from the ‘Open Scaffolds’ collection against the exsheathed third-stage larvae (xL3s) of Haemonchus contortus using recently developed whole-organism screening assays. We identified a hit compound, called SN00797439, which was shown to reproducibly reduce xL3 motility by ≥ 70%; this compound induced a characteristic, “coiled” xL3 phenotype (IC50 = 3.46–5.93 μM), inhibited motility of fourth-stage larvae (L4s; IC50 = 0.31–12.5 μM) and caused considerable cuticular damage to L4s in vitro. When tested on other parasitic nematodes in vitro, SN00797439 was shown to inhibit (IC50 = 3–50 μM) adults of Ancylostoma ceylanicum (hookworm) and first-stage larvae of Trichuris muris (whipworm) and eventually kill (>90%) these stages. Furthermore, this compound completely inhibited the motility of female and male adults of Brugia malayi (50–100 μM) as well as microfilariae of both B. malayi and Dirofilaria immitis (heartworm). Overall, these results show that SN00797439 acts against genetically (evolutionarily) distant parasitic nematodes i.e. H. contortus and A. ceylanicum [strongyloids] vs. B. malayi and D. immitis [filarioids] vs. T. muris [enoplid], and, thus, might offer a novel, lead-like scaffold for the development of a relatively broad-spectrum anthelmintic. Our future work will focus on assessing the activity of SN00797439 against other pathogens that cause neglected tropical diseases, optimising analogs with improved biological activities and characterising their targets.

Original languageEnglish
Pages (from-to)286-294
Number of pages9
JournalInternational Journal for Parasitology: Drugs and Drug Resistance
Volume7
Issue number3
DOIs
Publication statusPublished - 1 Dec 2017

Keywords

  • Anthelmintic
  • Haemonchus
  • Nematodes
  • Whole organism screening
  • ‘Open Scaffolds’ compound collection

Cite this

Preston, Sarah ; Jiao, Yaqing ; Baell, Jonathan B. ; Keiser, Jennifer ; Crawford, Simon ; Koehler, Anson V ; Wang, Tao ; Simpson, Moana M. ; Kaplan, Ray M. ; Cowley, Karla J. ; Simpson, Kaylene J ; Hofmann, Andreas ; Jabbar, Abdul ; Gasser, Robin Beat. / Screening of the ‘Open Scaffolds’ collection from Compounds Australia identifies a new chemical entity with anthelmintic activities against different developmental stages of the barber's pole worm and other parasitic nematodes. In: International Journal for Parasitology: Drugs and Drug Resistance. 2017 ; Vol. 7, No. 3. pp. 286-294.
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title = "Screening of the ‘Open Scaffolds’ collection from Compounds Australia identifies a new chemical entity with anthelmintic activities against different developmental stages of the barber's pole worm and other parasitic nematodes",
abstract = "The discovery and development of novel anthelmintic classes is essential to sustain the control of socioeconomically important parasitic worms of humans and animals. With the aim of offering novel, lead-like scaffolds for drug discovery, Compounds Australia released the ‘Open Scaffolds’ collection containing 33,999 compounds, with extensive information available on the physicochemical properties of these chemicals. In the present study, we screened 14,464 prioritised compounds from the ‘Open Scaffolds’ collection against the exsheathed third-stage larvae (xL3s) of Haemonchus contortus using recently developed whole-organism screening assays. We identified a hit compound, called SN00797439, which was shown to reproducibly reduce xL3 motility by ≥ 70{\%}; this compound induced a characteristic, “coiled” xL3 phenotype (IC50 = 3.46–5.93 μM), inhibited motility of fourth-stage larvae (L4s; IC50 = 0.31–12.5 μM) and caused considerable cuticular damage to L4s in vitro. When tested on other parasitic nematodes in vitro, SN00797439 was shown to inhibit (IC50 = 3–50 μM) adults of Ancylostoma ceylanicum (hookworm) and first-stage larvae of Trichuris muris (whipworm) and eventually kill (>90{\%}) these stages. Furthermore, this compound completely inhibited the motility of female and male adults of Brugia malayi (50–100 μM) as well as microfilariae of both B. malayi and Dirofilaria immitis (heartworm). Overall, these results show that SN00797439 acts against genetically (evolutionarily) distant parasitic nematodes i.e. H. contortus and A. ceylanicum [strongyloids] vs. B. malayi and D. immitis [filarioids] vs. T. muris [enoplid], and, thus, might offer a novel, lead-like scaffold for the development of a relatively broad-spectrum anthelmintic. Our future work will focus on assessing the activity of SN00797439 against other pathogens that cause neglected tropical diseases, optimising analogs with improved biological activities and characterising their targets.",
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Screening of the ‘Open Scaffolds’ collection from Compounds Australia identifies a new chemical entity with anthelmintic activities against different developmental stages of the barber's pole worm and other parasitic nematodes. / Preston, Sarah; Jiao, Yaqing; Baell, Jonathan B.; Keiser, Jennifer; Crawford, Simon; Koehler, Anson V; Wang, Tao; Simpson, Moana M.; Kaplan, Ray M.; Cowley, Karla J.; Simpson, Kaylene J; Hofmann, Andreas; Jabbar, Abdul; Gasser, Robin Beat.

In: International Journal for Parasitology: Drugs and Drug Resistance, Vol. 7, No. 3, 01.12.2017, p. 286-294.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Preston, Sarah

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